This project examines whether inadequate dietary intake of omega-3 essential fatty acids increases the risk for pathological traits and behaviors associated with alcoholism, specifically depression, aggression and suicide. Randomized placebo-controlled clinical intervention trials continue to be conducted in adult populations of aggressive alcoholics, women with depression during pregnancy and suicide attempters. These studies have been stimulated by the discovery that there are large differences in the prevalence of several psychiatric disorders amongst populations with high or low measurese of seafood consumption, which was further verified by examinations of omega-3 fatty acid tissue concentrations in epidemiological studies. Furthermore, it has been found that nutritional inadequacies during early development may leave residual neuropsychiatric deficits which contribute to an increased predisposition toward psychiatric disorders in adulthood. Developmental outcome studies are discussed below. In our ongoing clinical trial of aggressive alcoholics, the key questions are to assess if treatment with 2.8 g/d of omega-3 fatty acids will reduce 1) aggressive behaviors, 2) improve neurochemical measures of serotonergic function, and 3) improve cardiovascular measures thought to be associated with depressive and violent behaviors. This protocol is active and has enrolled 47 subjects with 100% tracking of data. Preliminary results indicate that anger is reduced by 33% (p<0.0008) and that there is a trend towards reduction in number of relapse days (55%, p= ns). Completion of the study is estimated for autumn 2007. In collaboration with Garth Bissette, PhD, we determined that low plasma DHA levels predict elevated levels of corticotrophin releasing hormone in the CSF of perpetrators of domestic violence. This finding, now in press, may lead to down regulation of the HPA axis through dietary changes. This proposition is currently being tested in our placebo-controlled, intervention trial of aggressive alcoholics. In collaboration with Laure-Budens Branchey, M.D., we published that low plasma levels of DHA and AA predicted relapse among cocaine and alcohol dependent subjects over the course of two years. Preliminary results of a placebo controlled clinical trial with Dr. Branchey indicates that anger scores are reduced by 50% over 4 months. In a collaborative trial among subjects admitted to an emergency room with deliberate self harm, we found that 2 g/d of omega-3 fatty acids reduced future suicidal thinking, anger and depression scores while improving positive outlooks to life. Mothers can become depleted of omega-3 essential fatty acids during pregnancy when their dietary intake is inadequate. Dietary deficiencies may increase the risk of depressive symptoms for the mothers. Preliminary data is available from an open trial of omega-3 fatty acids among women with depression during pregnancy currently being conducted in collaboration with Marlene Freeman, MD at the University of Arizona. Depressive symptoms were reduced an average of 43.5 % during 8 weeks of treatment. These findings are significant as they offer a treatment for depression during pregnancy that is not only non-toxic, but has additional health benefits to pregnant women and their babies. These findings are being followed up with a randomized, controlled trial which has enrolled n=20 subjects. The results of these interventional trials were predicted from data from an epidemiological study of the dietary intake of omega-3 fatty acids during pregnancy among nearly 14,500 women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). In clear dose-response relationships, deficient intakes were associated with nearly a doubling of the risk of depressive symptoms (EPDS >12) at 32 weeks gestation (p<1.4 X 10-17) and 18 weeks gestation and at both 8 weeks and 8 months postpartum. Findings were robust after rigorous examination of potential confounding factors. Deficient intake of omega-3 essential fatty acids during early development may also have adverse residual effects on the behaviors of children. In collaboration with the ALSPAC study, we found that deficient intake of omega-3 fatty acids during pregnancy were related to a doubling of the risk of adverse behavioral disorders among children at both 3.5 and 7 years of age. A dose response relationship predicted such parameters as increased risk of conduct disorders: fighting, lying, stealing, disobedience, which are well recognized risk factors for future sociopathic and criminal behaviors. We have collaborated with Marc Schuckit, M.D and Jean Golding, Ph.D. in designing a study to prospectively capture initial drinking behavior of these children as they enter adolescence. These data can be evaluated to determine if inadequate intake during pregnancy or early childhood is a risk factor for future substance abuse. If this is identified as a risk factor, prevention studies can be planned. A significant finding was that compliance with the FDA and EPA advisory for women to limit seafood consumption during pregnancy, to avoid methyl-mercury, inadvertently creates harm in the specific developmental domains in which protection was intended. The ALSAPC study was examined by either compliance or exceeding intake described by the advisory. These finding are currently being prepared for publication. In a prior cross-national analysis we found higher rates of homicide mortality were correlated to lower rates of seafood consumption. In order to further refine this finding we utilized the observation that the omega-6 fatty acids from seed oils compete for space in the tissues with omega-3 fatty acids, which are rich in seafood. We found that from 1950 to 2000, the increasing rates of homicide mortality were closely correlated with increasing availability omega-6 fatty acids in the food supply, in the USA, the United Kingdom, Australia and Canada. This association is also consistent with observational and interventional data for violence and hostility published by other investigators. In collaboration with Dr. Carlos Iribarren, we examined the dietary intake of omega-3 fatty acids and behavioral correlates among the 4,000 subjects in the CARDIA trial. Lower intake of DHA and other omega-3 fatty acids predicted a doubling of the risk of reporting clinically significant measures of hostility. In an intervention trial conducted in collaboration with Dr. Muldoon at the University of Pittsburgh, subjects with hypercholesterolemia were given either Simvistatin, (a cholesterol lowering drug) or a placebo for 8 weeks. We quantified changes in mood, cognition and plasma concentrations of essential fatty acids. Treatment with Simvistatin lowered total fatty acid concentrations, but spared DHA and AA. The relationship between the sparing of these essential fatty acids and improvements or decrements in mood and cognition are still under examination.